Previous studies of the pathway of gluconeogenesis in guinea pig liver have indicated important differences between this species and the more widely studied rat liver. One difference is in the potential regulatory role of mitochondrial P-enolpyruvate carboxykinase in the guinea pig liver. Since human liver also has a large proportion of this enzyme within the mitochondria the use of the guinea pig liver as model for understanding the regulation of gluconeogenesis in man is suggested. In this project the effect of fatty acids, glucagon and a variety of factors which alter the mitochondrial oxidation-reaction state in guinea pig liver will be tested for a potential regulatory role in gluconeogenesis. Liver perfusion studies using the guinea pig liver will also permit an analysis of the alterations in the intracellular concentration of critical intermediates in the over-all pathway of hepatic gluconeogenesis. Based on these studies we hope to develop a model for the regulation of glucose synthesis in mammalian liver which may be applicable to species such as man which have a large proportion of this hepatic P-enolpyruvate carboxylase within the mitochondria.